PROCESS FOR RECOVERY OF IOPROMIDE, SUITABLE FOR PHARMACEUTICAL PURPOSES, FROM MOTHER LIQUORS

PROCEDE DE RECUPERATION D'IOPROMIDE, A PARTIR DE SOLUTION-MERE, CONVENANT A DES FINS PHARMACEUTIQUES

English Abstract

This invention describes a process for recovery of iopromide, suitable for
pharmaceutical purposes, by heat treatment of the mother liquors or the
secondary
crystallizate in a reactor and subsequent crystallization.

French Abstract

La présente invention concerne un procédé de récupération d'iopromide à usage pharmaceutique par traitement thermique des eaux mères ou du produit de cristallisation secondaire dans un réacteur puis par cristallisation.

Claims

7
The embodiments of the invention in which an exclusive property or privilege
is
claimed are defined as follows:
1. A process for recovery of iopromide, the process comprising:
crystallizing dissolved secondary or subsequent crystallizate from an
iopromide mother
liquor, after heat treatment of said dissolved secondary or subsequent
crystallizate in a
tubular flow reactor;
wherein the iopromide contains atropisomeric forms in an amount of 40 to 51%
isomer
1 and 49 to 60% isomer 2.
2. A process according to claim 1, wherein the iopromide that is contained
in the
mother liquor or the secondary or subsequent crystallizate has an isomeric
ratio that is
outside the range of ratios defined in claim 1.
3. A process according to claim 1, wherein the heat treatment in a tubular-
flow
reactor is carried out at 100 to 300° C.
4. A process according to claim 1, wherein the crystallization is carried
out from an
alcohol.
5. A process according to claim 1, wherein the iopromide suitable for
pharmaceutical purposes is obtained by temperature treatment of atropisomers
that are
dissolved in a solvent.
6. A process according to claim 5, wherein a hydrodynamic dwell time of the
atropisomers that are dissolved in a solvent in the tubular-flow reactor is 1
to 60 minutes.
7. A process according to claim 6, wherein water is used as a solvent.
8. A process for recovery of iopromide, the process comprising:
crystallizing iopromide from mother liquor, dissolving said iopromide in a
solvent, heat
treating said dissolved iopromide in a tubular flow reactor, and crystallizing
iopromide;

8
wherein the crystallized iopromide contains atropisomeric forms in an amount
of 40 to
51% isomer 1 and 49 to 60% isomer 2.

Description

CA 02630413 2008-05-20
Process for Recovery of Iopromide, Suitable for Pharmaceutical Purposes, from
Mother Liquors.
The invention relates to a process for recovery of iopromide, suitable for
pharmaceutical purposes, by heat treatment of mother liquors or dissolved
secondary
crystallizate in a reactor and subsequent crystallization.
lopromide, 5-methoxyacetylamino-2,4,6-triiodo-isophthalic acid-[(2,3-dihydroxy-
N-methyl-propy1)-(2,3-dihydroxypropyl)]-diamide, (DE 196 41 178 C and EP 0 015
867
B), is an iodine-containing x-ray contrast medium with the following chemical
structure:
I Li
0 N \ OH
1
/0j .1
OH
0
lopromid
[Iopromide]
The bulky iodine atoms prevent, to a great extent, the free rotation of the
bond,
identified by 1 in the structural formula, between the aromatic ring and the
amide group
with the dihydroxypropyl-methylamino group by the presence of the N-methyl
group, so
that two atropisomers that are thermally quite stable occur. Such atropisomers
are
described in, i.a., "Recent Advances in Atropisomerism" by M. Oki in the
journal
"Topics in Stereochemistry," 1983, Volume 14, pages 1-81, and Tetrahedron
Letters No.
38, pages 4593-4598, 1966. In the case of one of the atropisomers, the
substituted

CA 02630413 2008-05-20
2
nitrogen atom lies above the ring plane; with other isomers, it lies below the
ring plane.
The two atropisomeric compounds (isomer 1 and isomer 2) are different in their
physical
properties, especially in their solubilities in water and organic solvents.
Only iopromide
of a certain composition relative to these atropisomers is allowed as an x-ray
contrast
medium (40-51% isomer 1 and 49-60% isomer 2).
Iopromide for pharmaceutical purposes is obtained by crystallization from
ethanol. In this connection, a mixture that consists of about 48% isomer 1 and
about 52%
isomer 2 accumulates regularly. The mother liquor contains the isomer 1 at
about 60%
and the isomer 2 at only up to about 40%. For this reason, only a secondary
crystallizate
with a false composition relative to the atropisomers can be recovered from
the mother
liquor (contains too much isomer 1).
In the production of iopromide, a final crystallization that consists of
alcohol is
performed herein. In this connection, a proportion of about 10% of iopromide
remains in
dissolved form in the mother liquor, which becomes apparent as a loss of
yield.
Earlier tests -- to crystallize out additional iopromide from the accumulating
mother liquors by secondary crystallization and thus to increase the yield --
failed, since
the iopromide K2 recovered from the mother liquors is not in accordance with
specifications with respect to the atropisomeric ratio. This behavior can be
attributed to
the fact that certain atropisomers preferably accumulate in the mother liquor.
Object of the Invention:
The production processes for iopromide that are known from the prior art
herein
exhibit the drawback that a higher loss in yield must be tolerated and no
technical process

CA 02630413 2012-10-04
3
exists that allows iopromide, which is in accordance with specifications with
respect to
the atropisomeric ratio and thus can be used for pharmaceutical purposes, to
be recovered
from the mother liquors.
Resolution of the Invention:
The above-described drawbacks could be resolved, surprisingly enough, in that
first a K2 is recovered from the iopromide, pure mother liquor, by a suitable
secondary
crystallization, which then is isomerized in a continuous tubular-flow reactor
in
accordance with specifications by a suitable heat treatment, without
significant
decomposition of the substance occurring.
According to one aspect of the invention, there is provided a process for
recovery
of iopromide, the process comprising:
crystallizing dissolved secondary or subsequent crystallizate from an
iopromide mother
liquor, after heat treatment of said dissolved secondary or subsequent
crystallizate in a
tubular flow reactor;
wherein the iopromide contains atropisomeric forms in an amount of 40 to 51%
isomer
1 and 49 to 60% isomer 2.
According to another aspect of the invention, there is provided a process for
recovery of iopromide, the process comprising:
crystallizing iopromide from mother liquor, dissolving said iopromide in a
solvent, heat
treating said dissolved iopromide in a tubular flow reactor, and crystallizing
iopromide;
wherein the crystallized iopromide contains atropisomeric forms in an amount
of 40 to
51% isomer 1 and 49 to 60% isomer 2.
The invention thus contains a process for recovery of iopromide and iopromide
mother liquors, suitable for pharmaceutical purposes, or solutions of the
secondary and
subsequent crystallizates by heat treatment of the solution, preferably in a
tubular-flow
reactor at 100-300 C, advantageously at 200-220 C, and then quick cooling to
room
temperature and crystallization. The heat treatment in a flow reactor is
advantageously
carried out in aqueous solution at hydrodynamic dwell times of 1 to 60
minutes.
Preferably the atropisomers are dissolved in a solvent. More preferably, the
solvent is
water. The total yield of iopromide can be increased quite significantly by
this process
according to the invention, such that the economic efficiency increases. In
addition, less
halogen-containing waste accumulates.

CA 02630413 2012-10-04
3a
The scope of the claims should not be limited by the preferred embodiments set
forth in the examples, but should be given the broadest interpretation
consistent with the
description as a whole.
Brief Description of the Drawing:
Fig. 1 illustrates an experimental set-up for heat isomerization of the
iopromide
secondary crystallizate.
Description of the Process in Detail:
First, a secondary crystallizate is recovered from the iopromide, pure mother
liquors, by the ethanolic mother liquors being concentrated by evaporation by
the factor

= CA 02630413 2008-05-20
=
4
2-16 and being dissolved in an alcohol at elevated temperature. Examples of
suitable
alcohols are alkanols such as methanol, ethanol, 1-propanol, 2-propanol, I-
butanol, and
2-butanol. Ethanol, 1-propanol and 2-propanol are preferably used, especially
preferably
1-propanol, since the crystallization from this solvent takes place especially
quickly and
completely and thus is economical. To achieve the crystallization, it can be
completely
inoculated with iopromide. The K2 crystallizate is then isolated, washed and
dried
according to known methods.
Example 1:
Production of the K2 Crystallizate
12,000 g of iopromide, pure mother liquor (solid content about 6.2%), is
concentrated by evaporation in a vacuum to form viscous oil of 892 g. 877 g of
this
residue is mixed in a suitable reaction vessel at a bath temperature of 65 C
with 439 ml
--of 1-propanol while being stirred. After inoculation with 0.73 g of
iopromide, it is fully
stirred for another 48 hours at a bath temperature of 65 C. The crystal
suspension is then
cooled to 20 C, stirred for 1 hour at this temperature and suctioned off via a
suction filter.
After washing with 4 portions of 110 ml of ethanol, the secondary
crystallizate is dried at
40 C in a vacuum-drying oven.
Yield: 363.8 g (about 52% of the experiment)
The secondary crystallizate that is obtained from the mother liquor has the
following atropisomeric ratio:

CA 02630413 2008-05-20
HPLC Specification Result
Isomer 1 40.0 ¨ 51.0% 62.2 %
Isomer 2 49.0 ¨ 60.0% 37.8%
The recovered secondary crystallizate is then brought into solution, i.e.,
dissolved
in water and heat-isomerized in a pressure-resistant, suitably designed,
continuously-
operating tube reactor. In this connection, hydrodynamic dwell times of 1 to
60 minutes,
preferably 1-30 minutes, especially preferably 1 to 10 minutes, are set at
temperatures of
between 100 to 300 C, preferably 150 C to 250 C, preferably 180 C to 230 C,
especially
preferably 200 C to 220 C. In a downstream heat exchanger, the heat-treated
iopromide
K2 solution is then quickly cooled to room temperature.
Example 2:
Heat-Isomerization of the Iopromide Secondary Crystallizate
280 g of iopromide-K2 from Example I is dissolved in 520 g of water. The
solution is then pumped at a volumetric flow rate of 3 ml/minute through a
flow pipe that
is provided with a pressurization valve of 20 bar at 208-209 C. The flow pipe
that is
used has an inside diameter of 1.7526 mm and a heated length Of 5.5 m (see
Figure 1).
A solution of the isomerized iopromide secondary crystallizate is then
purified via
ion-exchange columns and crystallized from ethanol.
The yield of the iopromide that is crystallized from ethanol is approximately
80%
of the experiment relative to the secondary crystallizate that is used in the
isomerization.

CA 02630413 2008-05-20
6
The crystallizate shows a content after HPLC (standard method) of greater than
97.5% relative to the external standard and has the following atropisomeric
ratio:
HPLC Specification Result
Isomer 1 40.0 ¨ 51.0% 49.4%
Isomer 2 49.0¨ 60.0% 50.6%

Representative Drawing